This invention relates to a process for the inititation of oestrus and ovulation early postpartum, especially but not exclusively, in dairy cows. The invention also relates to methods of increasing milk production.
Reproductive performance is one of the important factors determining the profitability of dairy herds. Ideally, the calving interval should average one year, but this can only be achieved if the pregnancy success and detection rate of oestus are high and the interval between parturition and first service is less than 90 days (Bulman, D. C. and Lamming G. E. J Reprod. Fert (1978) 54: 447-58).
In milked cows, there is a suppression of ovarian follicular development for a variable period after parturition and there is current evidence that a significant number of animals (about 12%) exhibit prolonged anovulatory periods postpartum (PP) (Royal, M. D., et al., (1999) Animal Science). In dairy cows there are significant changes in plasma (lutenizing hormone) LH levels after parturition, directly related to the initiation of ovarian cycles, with low basal LH levels immediately postpartum followed by increases in mean levels and the development of clear LH episodes with increasing episode frequency (Peters A. R. et al., (1981) Journal of Reproduction and Fertility 62: 567-573). There is clear evidence that the low levels of progesterone, secreted as a result of the initiation of postpartum ovarian follicular development, contribute to establishing a normal oestrous cycle pattern (Lamming, G. E., et al., (1981) Journal of Reproduction and Fertility Supplement 30: 155-170). Furthermore, the incidence of the silent ovulation in cycles prior to insemination delays the intervals to first PP insemination and conception (Senger, P. L. (1994) Journal of Dairy Science 77: 2745-2753).
There is a marked interdependence of activity between the ovaries and the uterus shortly after parturition in mammals such as cows. The early resumption of ovarian activity leading to the availability of circulating oestradiolxe2x80x9417xcex2, may help to hasten uterine involution through a reduction in size, a marked increase in uterine tone (for a review see Hussein, A. M. (1989) J. Vet Med 36: 641-451) and benefits to the uterine defence mechanisms (Rowson, L. E. A. et al., (1953) Veterinary Record 65: 335-341). Similarly, the interval to post partum (PP) uterine involution is significantly correlated with the occurrence of the first PP ovulation (Madej, A. et al., (1984) Theriogenology 21: 279-287; Buch, N. C. et al., (1955) Journal of Dairy Science 38: 73-79). An early return to ovarian cyclicity PP was found by most workers to be associated with high fertility (Thatcher, W. W. and Wilcox, C. J., (1973) Journal of Dairy Science 56: 608-610; Stevenson, J. S. and Call, E. P. (1983) Theriogenology 19: 367-375; Staples, C. R et al., (990) Journal of Dairy Science 73: 938-947; Senatore, E. M. et al., (1996) Animal Science 62: 17-23; Darwash, A. O. et al., (1997) Animal Science 65: 9-16; Kinsel, M. L. and Etherington, W. G. (1998) Theriogenology 50: 1221-1238; Mann, G. E. et al., (1998) Nottingham Cattle Fertility Conference 11-12. Based on this premise, a number of workers have used prostaglandin F2xcex1. (PGF2xcex1) administration in an attempt to induce early postpartum uterine recovery or alternatively progesterone (P4) to initiate early return to a pattern of normal oestrous cycles, but with inconsistent results. Where a prostaglandin alone has been supplied, it has been reported that a single dose of PGF2xcex1 administered prior to day 40 postpartum is beneficial to herd fertility Young, I. M. et al., (1984) Veterinary Record 115: 429-431; Bernard, M. and Stevenson, J. S. (1986) Journal of Dairy Science 69: 800-811; Young, I. M. and Anderson, D. B. (1986) Veterinary Record 115: 429-431; Etherington, W. G. et al., (1988) Theriogenology 29: 565-575; MeClary, D. G. et al., (1989) Theriogenology 31: 565-570; White, A. J. and Dobson, H. (1990) Veterinary Record 24: 588-592; Etherington, W. G. et al., (1994) Theriogenology 42: 739-752; Pankowski et al., (1995) Journal of Dairy Science 78: 1477-1488, but others have concluded that Here was no significant improvement (Mortimer et al., (1984) Theriogenology 21: 869-874; Macmillan et al., (1987) Proceeding of the New Zealand Society of Animal Production 47: 65-68; Stevenson, J. S. and Call, E. P. (1988) Journal of Dairy Science 71; 1926-1933; Armstrong et al., (1989) Veterinary Record 125: 597-600; Morton et al., (1992) Australian Veterinary Journal 69: 158-160).
Similarly, the administration of P4 during the PP period is designed to initiate an early return to normal function of the hypothalamic-pituitary-ovarian axis considered necessary for the early initiation of oestrus, ovulation and luteal activity. However, the use of a progeterone-releasing intra-vaginal device (PRID) on Days 10 to 15 PP (Kyle, S. D. (1992) Journal of Dairy Science 75: 1456-1460 or on Days 5 to 15 PP (Stevenson, J. S. and Purseley, R. (1994) Journal of Dairy Science 77: 726-734) did not include the expected early ovulation compared with untreated animals. The latter workers reported a significant increase in the number of treated animals showing overt oestrus at the first PP ovulation compared with untreated controls (64 vs 20%).
In an attempt to improve fertility through the induction of a cyclic ovarian pattern early PP, a protocol was developed by the inventors utilising a sequence of PGF2. and controlled internal drug (progesterone) release (CIDR). Prostaglandin was chosen because of its cleansing effect on the uterine environment (Gustaffson, B. et al., (1976) Theriogenology 6: 45-50; Etherington, W. G., et al., (1985) Canadian Journal of Comparative Medicine 49: 261-267) and in the promotion of uterine involution (Lindell, J. O. and Kindhal, H. (1983) Theriogenology 24: 269-274; Bonnet, B. N., et al., (1990) Theriogenology 33: 877-890) while a short period (7 days) of progesterone treatment using CIDR was designed to stimulate the short luteal phases frequently observed in PP cows (Lamming, G. E., et al., (1981) Journal of Reproduction and Fertility (Supplement) 30: 155-170; Eger, M., et al., (1988) Animal Reproductive Science 16: 215-224). Furthermore, CIDR insertion for five days was found to increase the oestrous response to subsequent PGF2xcex1 treatment (Zu, Z. Z., et al., (1997) Theriogenology 47: 687-701).
Folman et al., (Anim. Reprod. Sci., 4, 117-26, 1981), discloses a method of synchronising oestrus in cows, wherein prostaglandin is given late post partum (after 60 days) followed by progesterone. No indication is given suggesting that by giving prostaglandin early post partum followed by progesterone that ovulation and oestrus can be initiated.
Johari et al., (Malay. Agric. Res. Dev. Inst., Res. J., 18, 117-122, 1990) discloses a method of synchronising oestrus late post partum (60-90 days) comprising giving progesterone followed by prostaglandin.
The object of the present invention is to initiate ovarian hormone cycles in cows during the early post partum period; previously claimed to be conducive to improved reproductive performance (Stevenson, J. S. and Call, E. P. (1983) Theriogenology 19: 367-375, Darwash, A. O. et al., (1997) Animal Science 65: 9-16).
However, the concept that an early return to PP ovarian cyclicity is conducive to higher fertility has recently been challenged by Smith, M. C. A. and Wallace, J. M. (1998) Reproductive Fertility Development 10: 207-216 and their findings, albeit on a limited number of animals, merit scrutiny. These authors showed from milk P4 analysis of a single herd that multiparous cows ovulating before 21 days PP exhibited poorer reproductive performance than similar animals ovulating later, an effect not observed in their primiparous cows. In the multiparous PP cows, there was a high incidence of persistent corpora lutea (PCL), a finding we have confirmed by study of a wider progesterone database involving several herds, which showed a significant increased incidence of PCL in PP cows between 1975 to 1982 and 1996 to 1998 (Royal, M. D. et al., (1999) Animal Science (in press). The incidence of PCL during the PP period has been associated with a lower submission rate for insemination, longer intervals to conception, lower pregnancy rates and a higher incidence of embryo loss and therefore, a higher culling rate (Lamming, G. E. and Darwash, A. O. (1998) Animal Reproduction Science 52: 175-190). These trends may be influenced by recent changes in the genetic structure and milk production merit of all UK dairy herds, or associated with an increased incidence of PP uterine dysfunction. The ideal scenario for maximum fertility is an early return to ovarian cyclicity in the PP cow in which the uterus has fully involuted and in the absence of uterine infection. From knowledge of the influence of a persistent uterine infection on the rate of uterine involution, a cow with a persistent uterine infection which ovulates by Day 21 postpartum may be expected to experience a delayed luteolysis, therefore a delay in the return to a normal ovarian cyclic pattern. Thus in herds where there is an increased incidence of PCL it can be expected that fertility parameters and pregnancy rates will be adversely affected. The use of intramuscular (i.m.) injection of PGF2xcex1 in methods of the present invention is designed to decrease the chances of delayed uterine involution and persistent uterine infection.
The inventors have found that a treatment protocol typically using a single intramuscular injection of PGF2xcex1 (Estrumate) on Days 12-14 PP followed two days later by progesterone (CIDR) for 7 days was effective in initiating ovarian cyclicity, reducing the interval to postpartum oestrus and intervals to first insemination and conception (P less than 0.05). The treatment protocol will initiate early ovarian cyclicity, improve heat detection efficiency, and therefore enhance reproductive performance, particularly in large herds using a block caving management regime.
According to one aspect of the present invention there is provided a method of initiating oestrus in a female mammal, the method comprising supplying a prostaglandin post partum and subsequently treating with progesterone or a equivalent thereof.
According to another aspect of the invention there is provided a method of increasing milk production in a female mammal, the method comprising supplying a prostaglandin or prostaglandin analogue post partum and subsequently treating with progesterone or a functional equivalent thereof
There are two distinct aspects of the treatment protocol in methods according to the invention; PGF2xcex1 injections to ensure an adequate uterine environment prior to P4 administration, and P4 to ensure sensitisation of the hypothalamic-pituitary-ovarian axis, to facilitate follicle development, ovulation and the manifestation of oestrus. The protocol may be applied so that animals would ovulate by Day 25 postpartum.
The mammal may be from a domesticated species, particularly a cattle species, most preferably a dairy cow.
The prostaglandin may be for example prostaglandin PGF2xcex1 or may be a synthetic analogue thereof e.g. dinoprost, cloprostenol, luprostiol, tiaprost, etiproston tromethaline.
The prostaglandin may be supplied on any one of days 12, 13, 14 or 15 post partum. The prostaglandin may be supplied by any suitable delivery route but is preferably supplied parenterally. The term parenteral, and cognate terms, as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. Most preferably the prostaglandin is supplied by intra-muscular injection. The prostaglandin is preferably supplied at a dose of about 500 xcexcg (or a suitable dose of analogue is supplied to give an equivalent effect).
The term xe2x80x9cprogesteronexe2x80x9d used herein includes natural and synthetic compounds having relevant biological activity of a naturally occurring progesterone and includes progesterones isolated or derived from other species. The progesterone or progesterone equivalent may be supplied 36-60 hrs, preferably 42-54 hrs most preferably about 48 hrs after the supply of the prostaglandin.
Preferably, the progesterone is supplied by a controlled internal drug release device. The device may be in the form of a plastic intravaginal device or may be in the form of or include another controlled/sustained release system such as microcapsules, liposomes, implants, microspheres or the like.
The progesterone or progesterone equivalent may be supplied for 6 to 9 days, preferably 7 days. Where the progesterone is supplied by a controlled internal drug release device, that device may be removed after 6 to 9 days preferably after 7 days. Where the progesterone is supplied by another controlled/sustained release system that system may be arranged to stop or reduce the release of progesterone.
The progesterone may be supplied to give a milk progesterone level of 5 xcexcg/l.
Preferred progesterone equivalents include:
flugestone acetate
medroxyprogesterone acetate
altrenogest
norgestamet
According to another aspect of the invention there is supplied a kit for use in initiating oestrus in post partum mammals, or for improving milk production in mammals, the kit comprising a prostaglandin or analogue and a progesterone or an equivalent thereof. The prostaglandin may be supplied in a form for parenteral administrationxe2x80x94preferably intramuscular injection. The progesterone or equivalent may be in a form for controlled internal release. Preferably, the progesterone or equivalent is in a form by which it can be delivered for seven days.
Preferably the kit is arranged to supply a single dose of about 500 xcexcg of the prostaglandin PGF2 or its equivalent.
The kit is preferably arranged to supply about 1.9 g of a progesterone or progesterone equivalent over the treatment period.